The corneal epithelium is one of the most sensitive and critical structures of the eye. Currently, the pathways that regulate the differentiation and renewal of the corneal epithelial cells are largely unknown. Understanding the precise regulatory pathways governing corneal epithelial regeneration is critical for the development of effective treatments for many corneal wound healing disorders. Notch signaling, which is an important pathway in cell-fate determination, has recently been implicated in corneal epithelial growth and differentiation. The long-term objective of this application is two fold. First, is to contribute to the development of novel and innovative treatments for patients with ocular surface disease by defining the role of Notch signaling in the regulation of corneal epithelial growth and differentiation. Second, is to further develop the career of the applicant as a clinician-scientist and facilitate his transition to becoming an independent investigator. To accomplish the research objectives of this application, the following three specific aims will be pursued: (1) Determine the expression of Notch receptors and ligands in the corneal epithelial cells during proliferation and differentiation. (2) Characterize the effects of induced Notch activation and inhibition on the growth and differentiation of the human corneal epithelial cells. (3) Determine the in vivo effects of Notch activation and inhibition in the murine corneal epithelium. In addition to pursuing these specific aims, the applicant will follow a carefully designed career development plan involving didactic and hands-on training under the direct supervision of experienced mentors. Overall, these studies will improve our understanding of how the surface of the eye is regenerated. These results will lead to the development of new treatments for patients with disabling visual conditions involving the surface of the eye.